Aberrant activity of Trace Amine Associated Receptors (TAARs), especially for TAAR1 is associated with psychiatric conditions such as depression, anxiety disorders, bipolar disorder, attention deficit hyperactivity disorder (ADHD), stress-related disorders, psychotic disorders such as schizophrenia, neurological diseases such as Parkinson's disease, neurodegenerative disorders such as Alzheimer's disease, epilepsy, migraine, hypertension, substance abuse and metabolic disorders such as eating disorders, diabetes, diabetic complications, obesity, dyslipidemia, disorders of energy consumption and assimilation, disorders and malfunction of body temperature homeostasis, disorders of sleep and circadian rhythm, and cardiovascular disorders.
Some of the physiological effects (i.e. cardiovascular effects, hypotension, induction of sedation) which have been reported for compounds which may bind to adrenergic receptors (WO02/076950, WO97/12874 or EP 0717 037) may be considered to be undesirable side effects in the case of medicaments aimed at treating diseases of the central nervous system as described above. Therefore it is desirable to obtain medicaments having selectivity for the TAAR1 receptor vs adrenergic receptors. Objects of the present invention show selectivity for TAAR1 receptor over adrenergic receptors, in particular good selectivity vs the human and rat alpha1 and alpha2 adrenergic receptors.
The classical biogenic amines (serotonin, norepinephrine, epinephrine, dopamine, histamine) play important roles as neurotransmitters in the central and peripheral nervous system (Deutch, A. Y. and Roth, R. H. (1999) Neurotransmitters. In Fundamental Neuroscience (2nd edn) (Zigmond, M. J., Bloom, F. E., Landis, S. C., Roberts, J. L, and Squire, L. R., eds.), pp. 193-234, Academic Press). Their synthesis and storage, as well as their degradation and reuptake after release are tightly regulated. An imbalance in the levels of biogenic amines is known to be responsible for the altered brain function under many pathological conditions (Wong, M. L. and Licinio, J. Research and treatment approaches to depression, Nat. Rev. Neurosci. 2001 2:343-351; Carlsson, A. et al., Interactions between monoamines, glutamate, and GABA in schizophrenia: new evidence, Annu. Rev. Pharmacol. Toxicol. 2001 41:237-260; Tuite, P. and Riss, J., Recent developments in the pharmacological treatment of Parkinson's disease. Expert Opin. Investig. Drugs 2003 12:1335-1352, Castellanos, F. X. and Tannock, R., Neuroscience of attention-deficit/hyperactivity disorder: the search for endophenotypes, Nat. Rev. Neurosci. 2002 3:617-628). A second class of endogenous amine compounds, the so-called trace amines (TAs) significantly overlaps with the classical biogenic amines regarding structure, metabolism and subcellular localization. The TAs include p-tyramine, β-phenylethylamine, tryptamine and octopamine, and they are present in the mammalian nervous system at generally lower levels than classical biogenic amines (Usdin, Earl; Sandler, Merton; Editors. Psychopharmacology Series, Vol. 1: Trace Amines and the Brain. [Proceedings of a Study Group at the 14th Annual Meeting of the American College of Neuropsychoparmacology, San Juan, Puerto Rico] (1976)). Their dysregulation has been linked to various psychiatric diseases like schizophrenia and depression (Lindemann, L. and Hoener, M., A renaissance in trace amines inspired by a novel GPCR family, Trends in Pharmacol. Sci. 2005 26:274-281) and for other conditions like attention deficit hyperactivity disorder, migraine headache, Parkinson's disease, substance abuse and eating disorders (Branchek, T. A. and Blackburn, T. P., Trace amine receptors as targets for novel therapeutics: legend, myth and fact, Curr. Opin. Pharmacol. 2003 3:90-97; Premont, R. T. et al., Following the trace of elusive amines, Proc. Natl. Acad. Sci. U.S.A. 2001 98:9474-9475).
For a long time, TA-specific receptors had only been hypothesized based on anatomically discrete high-affinity TA binding sites in the CNS of humans and other mammals (Mousseau, D. D. and Butterworth, R. F., A high-affinity [3H] tryptamine binding site in human brain. Prog. Brain Res. 1995 106:285-291; McCormack, J. K. et al., Autoradiographic localization of tryptamine binding sites in the rat and dog central nervous system. J. Neurosci. 1986 6:94-101).
Accordingly, the pharmacological effects of TAs were believed to be mediated through the well-known machinery of classical biogenic amines, by either triggering their release, inhibiting their reuptake or by “crossreacting” with their receptor systems (Premont, R. T. et al., Following the trace of elusive amines, Proc. Natl. Acad. Sci. U.S.A 2001 98, 9474-9475; Dyck, L. E., Release of some endogenous trace amines from rat striatal slices in the presence and absence of a monoamine oxidase inhibitor. Life Sci. 1989 44, 1149-1156; Parker, E. M. and Cubeddu, L. X. (1988) Comparative effects of amphetamine, phenylethylamine and related drugs on dopamine efflux, dopamine uptake and mazindol binding, J. Pharmacol. Exp. Ther. 1989 245, 199-210). This view changed significantly with the recent identification of several members of a novel family of GPCRs, the trace amine associated receptors (TAARs). There are 9 TAAR genes in human (including 3 pseudogenes) and 16 genes in mouse (including 1 pseudogene). The TAAR genes do not contain introns (with one exception, TAAR2 contains 1 intron) and are located next to each other on the same chromosomal segment. The phylogenetic relationship of the receptor genes, in agreement with an in-depth GPCR pharmacophore similarity comparison, and pharmacological data suggest that these receptors form three distinct subfamilies (Lindemann, L. and Hoener, M. (2005) A renaissance in trace amines inspired by a novel GPCR family, Trends in Pharmacol. Sci. 26, 274-281; Lindemann, L. et al. (2005) Trace amine associated receptors form structurally and functionally distinct subfamilies of novel G protein-coupled receptors, Genomics 2005 85:372-385). TAAR1 is in the first subclass of four genes (TAAR1-4) highly conserved between human and rodents. TAs activate TAAR1 via Gαs. Dysregulation of TAs was shown to contribute to the etiology of various diseases like depression, psychosis, attention deficit hyperactivity disorder, substance abuse, Parkinson's disease, migraine headache, eating disorders, metabolic disorders and therefore TAAR1 ligands have a high potential for the treatment of these diseases.